Recent breakthroughs in stem cell biology have accelerated research in the area of regenerative medicine. Over the past years, it has become possible to derive patient-specific stem cells which can be used to generate different cell populations for potential cell therapy. Systems biological modeling of stem cell pluripotency and differentiation have largely been based on prior knowledge of signaling pathways, gene regulatory networks, and epigenetic factors. However, there is a great need to extend the complexity of the modeling and to integrate different types of data, which would further improve systems biology and its uses in the field. In this chapter, we first give a general background on stem cell biology and regenerative medicine. Stem cell potency is introduced together with the hierarchy of stem cells ranging from pluripotent embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to tissue-specific multipotent and unipotent stem cells. Secondly, we address some of the systems biological approaches which have already added valuable knowledge to the stem cell field. Particular attention is paid to the most commonly used knowledge-based models as well as to the unsupervised data-driven model. Finally, we will revisit the discovery of the iPSCs by Yamanaka in 2006 and superimpose a data-driven systems biological approach on the data which this amazing discovery was based on. This approach helps to demonstrate how systems biology can complement the field of stem cell biology.